Alzheimer's disease (AD) is a progressive degenerative disease of the central nervous system characterized clinically by dementia and neuropathologically by the presence of numerous senile plaques and neurofibrillary tangles. AD is typically a late onset disease of the elderly. However, a small number of pedigrees have been described wherein an early onset form of the disease is inherited as an autosomal dominant with age dependent penetrance. Most commonly, the age of onset of the disease is below 60 years old. Genetic factors have been implicated in both early and late onset AD.
Mutations in at least four different genetic loci are associated with an inherited susceptibility to AD. The e4 allele of the apolipoprotein E (ApoE) gene on chromosome 19 is associated with late onset AD (Strittmatter et al. Proc. Natl. Acad. Sci. USA 1993, 90:1977-1981; Saunders et al. Neurology 1993, 43:1467-1472); Corder et al. Science 1993, 261:921-923). Mutations in the .beta.-amyloid precursor protein (.beta.APP) gene on chromosome 21 have been found in a small number of families with early onset AD (Goate et al. Nature 1991, 349:704-706; Chartier-Harlin et al. Nature 1991, 353:844-846; Murrell et al. Science 1991, 254:97-99; Karlinsky et al. Neurology 1992, 42:1445-1453). Most recently, a novel AD locus in a gene referred to as STM2 was identified on chromosome 1 (1q31-41) from genetic linkage analysis of "Volga German" kindred (Ephrat Levy-Lahad et al. Science 1995, 269:970-973; ibid. 973-977). The STM2 gene bears a remarkable similarity to the AD-associated gene, S182.
The fourth locus (AD3) has been mapped by genetic linkage studies to chromosome 14q24.3 and may account for Lip to 70% of early-onset autosomal dominant AD. Schellenberg et al. Science 1992, 258:668-670; George-Hyslop et al. Nature Genet. 1992, 2:330-334; Van Boreckhoven et al. Nature Genet. 1992, 2:335-339). The AD3 locus is associated with the most aggressive form of this disease (onset between 30 and 60 years of age) and it has been suggested that mutations at this locus put into effect a biologically fundamental process leading to AD.
Recently, a novel gene with five missense mutations in seven pedigrees segregating early-onset autosomal dominant AD at the AD3 locus, the S 182 gene, was cloned and described by Sherrington et al. Nature 1995, 375:754-760. Analysis of the nucleotide sequence of the S182 transcript revealed heterozygous nucleotide substitutions in the reverse transcriptase-polymerase chain reaction products from affected members of six large pedigrees. The putative open reading frame (ORF) of S182 encodes a protein predicted to be a classical seven-transmembrane protein and the pedigree-associated nucleotide substitutions change the encoded amino acids in transmembrane (TM) helices II(L146M), VI(E246A), and VII(Y410C) and in loops between TMII-TMIII(R163H) and TMVI-TMVII(V286L). No transmembrane ion channel function has been demonstrated for S182 to date.
A number of other mutants of the S182 gene have now been identified. Genomic analysis of the S182 gene has defined the intron-exon boundaries of the primary transcription unit. This has led to the development of a method for identification of intronic polymorphisms which are predictive of disease as well as elucidation of several splicing variants and proximal coding mutations. These intronic sequences are useful in the early detection of mutant forms of the S182 gene, a gene which is usually associated with aggressive early-onset AD but may also be involved in the late onset of this disease as well.